Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
基本信息
- 批准号:10469579
- 负责人:
- 金额:$ 32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:A549AddressAgingAnabolismApoptosisBindingBiochemicalBiologicalBiologyBiomassCRISPR/Cas technologyCell Cycle ArrestCell ProliferationCell SurvivalCellsClinicClinicalComplexConsumptionDNA MethylationDNA Modification MethylasesDataDevelopmentDiabetes MellitusDiseaseDrug TargetingEnvironmentEnzymesEpigenetic ProcessEssential Amino AcidsExhibitsFRAP1 geneGenetic TranscriptionGlucoseGlutamineGoalsGrowthGrowth FactorHela CellsHomeostasisHumanHuman Cell LineImmunosuppressionIntronsIsotope LabelingLeadLinkLipidsMEL GeneMalignant NeoplasmsMammalian CellMeasuresMessenger RNAMetabolicMetabolic PathwayMetabolic syndromeMetabolismMethionineMethionine Metabolism PathwayMethylationMethyltransferaseModificationMolecularMutateNeurodegenerative DisordersNutrientObesityOrganPC3 cell linePathologicPathway interactionsPatientsPhosphorylation SitePhosphotransferasesPhysiologicalPositioning AttributeProcessProtein BiosynthesisProteinsProteomicsRNARNA InterferenceRNA methylationReactionRegulationReportingRibosomal RNARoleS-AdenosylmethionineSignal PathwaySignal TransductionSyndromeSystemTherapeuticTherapeutic InterventionTissuesTracerTranscriptional Regulationbasec-myc Genescell growthcell motilitychemical geneticsdietarydrug discoveryhistone methylationinhibitorinsightmacromoleculemetabolic ratemetabolomicsmethionine adenosyltransferasemouse modelneoplastic cellnervous system disordernovelnucleotide metabolismpre-clinicalside effectstable isotopetargeted treatmenttherapeutic targettumortumor growth
项目摘要
SUMMARY
The mechanistic target of rapamycin complex 1 (mTORC1) senses and integrates diverse environmental signals
to control energy and nutrient-consuming biosynthetic processes, such as protein, lipid, and nucleotide
synthesis. mTORC1 stimulates anabolic cell growth through posttranslational and transcriptional mechanisms
leading to increased macromolecule synthesis a prerequisite to augment cellular biomass priming cells for
growth and division. In many diseases, the prominence of mTORC1 signaling reinforces the importance of
considering targeting mTORC1 signaling in several diseases including neurodegenerative disorders, diabetes,
tumor syndromes, and aging. However, direct mTORC1 targeted therapies, being conceptually and preclinically
a promising target, displayed only limited efficacy in human patients. Therefore, a better understanding of the
biology downstream of mTORC1 and the development of more effective and specific therapeutic strategies in
the treatment of mTORC1-driven diseases are needed. To achieve the biosynthetic demands accompanying
proliferation, cells must increase the transport of nutrients from the environment. Glucose, lactate, and glutamine
are the principal nutrients that promote biosynthesis and survival in mammalian cells. An emerging aspect of
nutrient utilization in aging and proliferative diseases includes the role of dietary methionine restriction, which
was recently explored in the context of obesity, metabolic syndrome, and cancer. Methionine is an essential
amino acid that is catabolized and recycled in a sequence of metabolic reactions designated as the methionine
cycle. Methionine and ATP are converted into the universal methyl donor S-adenosylmethionine (SAM) via the
methionine adenosyltransferase 2 alpha (MAT2A) enzyme. Under this proposal, we propose to study the
influence of mTORC1 signaling on S-adenosylmethionine (SAM) synthesis and the subsequent methylation
processes supporting anabolic metabolism. We have identified that mTORC1 stimulates SAM synthesis in
various cell settings through direct transcriptional control of MAT2A expression by c-MYC. We propose to
evaluate the influence of mTORC1 signaling on SAM synthesis in a variety of human cells (Specific Aim1). Will
identify the mechanisms by which mTORC1 signaling promotes RNA methylation, particularly the N6-
methyladenosine (m6A) mark. We will determine the role of m6A on RNA downstream of mTORC1 in the control
of cell growth (Specific Aim2). Furthermore, we will determine the implication of the mTORC1-MAT2A axis on
tumor growth and the potential therapeutic strategy derived from this mechanism (Specific Aim3). Thus, the
overall goal of this proposal is to decipher the molecular mechanisms by which mTORC1 controls RNA
methylation in normal and pathological settings. We anticipate that the proposed studies will yield new insights
into how SAM levels alter anabolic metabolism and will uncover therapeutic targets to perturb mTORC1-driven
diseases.
总结
项目成果
期刊论文数量(0)
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{{ truncateString('Issam BEN-SAHRA', 18)}}的其他基金
Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
- 批准号:
10277131 - 财政年份:2021
- 资助金额:
$ 32万 - 项目类别:
Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
- 批准号:
10630233 - 财政年份:2021
- 资助金额:
$ 32万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
- 批准号:
10539252 - 财政年份:2020
- 资助金额:
$ 32万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
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10321274 - 财政年份:2020
- 资助金额:
$ 32万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
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